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Uses

Treatment of HIV Infection

Abacavir is used in conjunction with other antiretroviral agents for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults, adolescents, and pediatric patients 3 months of age or older.

Abacavir usually is used in conjunction with another HIV nucleoside reverse transcriptase inhibitor (NRTI) (dual NRTIs) and an HIV integrase strand transfer inhibitor (INSTI), HIV nonnucleoside reverse transcriptase inhibitor (NNRTI), or HIV protease inhibitor (PI) in INSTI-, NNRTI-, or PI-based regimens.

The fixed-combination preparation containing abacavir and lamivudine (abacavir/lamivudine; Epzicom) is used in conjunction with other antiretrovirals for the treatment of HIV-1 infection in adults and pediatric patients weighing 25 kg or more.

The fixed-combination preparation containing abacavir, dolutegravir, and lamivudine (abacavir/dolutegravir/lamivudine; Triumeq) is used alone as a complete treatment regimen or in conjunction with other antiretrovirals for the treatment of HIV-1 infection in adults 18 years of age or older.

The fixed-combination preparation containing abacavir, lamivudine, and zidovudine (abacavir/lamivudine/zidovudine; Trizivir) is used alone as a complete treatment regimen or in conjunction with other antiretrovirals for the treatment of HIV-1 infection in adults and adolescents weighing 40 kg or more.

Abacavir has been used in triple and quadruple NRTI regimens (i.e., single-class NRTI regimens) that include abacavir and 2 or 3 other NRTIs. However, there is evidence that triple or quadruple NRTI regimens have inferior virologic efficacy.(See All-NRTI Regimens under Treatment of HIV Infection: Antiretroviral-naive Adults and Adolescents, in Uses.)

Abacavir and fixed-combination preparations containing abacavir (abacavir/lamivudine, abacavir/dolutegravir/lamivudine, abacavir/lamivudine/zidovudine) should not be used in individuals who test positive for the human leukocyte antigen (HLA)-B*5701 allele.(See Precautions Related to Hypersensitivity Reactions under Cautions: Precautions and Contraindications.)

The most appropriate antiretroviral regimen cannot be defined for each clinical scenario and selection of specific antiretroviral agents for use in such regimens should be individualized based on information regarding antiretroviral potency, potential rate of development of resistance, known toxicities, and potential for pharmacokinetic interactions as well as virologic, immunologic, and clinical characteristics of the patient. For information on the general principles and guidelines for use of antiretroviral therapy, including specific recommendations for initial therapy in antiretroviral-naive patients and recommendations for changing antiretroviral regimens,

Antiretroviral-naive Adults and Adolescents

Dual NRTI Options

For initial treatment in HIV-infected adults and adolescents, the US Department of Health and Human Services (HHS) Panel on Antiretroviral Guidelines for Adults and Adolescents states that the dual NRTI option of abacavir and lamivudine is a recommended dual NRTI option for use in most INSTI-, NNRTI-, and PI-based regimens, but should be used only in patients who are HLA-B*5701 negative. This recommendation is based on safety and efficacy data from clinical trials, clinical experience, and availability of fixed combinations containing abacavir and lamivudine.

If the dual NRTI option of abacavir and lamivudine is used, the fixed combination containing both drugs (abacavir/lamivudine; Epzicom) can be used in adults and adolescents to decrease pill burden and increase adherence. Abacavir/lamivudine must be used in conjunction with other antiretrovirals for treatment of HIV-1 infection and should be used with a drug from another class (not another NRTI).

The HHS panel states that dolutegravir in conjunction with the dual NRTI option of abacavir and lamivudine (or emtricitabine) is a recommended INSTI-based regimen for initial treatment in antiretroviral-naive adults and adolescents, but should be used only in those who are HLA-B*5701 negative. These experts also state that ritonavir-boosted darunavir or cobicistat-boosted darunavir in conjunction with abacavir and lamivudine (or emtricitabine) are alternative PI-based regimens for initial treatment in antiretroviral-naive adults and adolescents, but should be used only in those who are HLA-B*5701 negative. Other regimen options involving the dual NRTI option of abacavir and lamivudine (or emtricitabine) that can be considered for initial treatment in antiretroviral-naive adults include ritonavir-boosted or cobicistat-boosted atazanavir, efavirenz, or raltegravir in conjunction with abacavir and lamivudine (or emtricitabine); however, these options should be used only in those who are HLA-B*5701 negative and have baseline plasma HIV RNA levels less than 100,000 copies/mL.

All-NRTI Regimens

Abacavir has been included in NRTI regimens that include 3 or 4 NRTIs (without any drugs from another class). However, triple and quadruple NRTI regimens are not recommended for initial treatment in HIV-infected adults or adolescents because such regimens have inferior virologic efficacy or have not been adequately studied. In addition, regimens that only include NRTIs are not usually recommended in antiretroviral-experienced patients.(See Antiretroviral-experienced Adults and Adolescents under Uses: Treatment of HIV Infections.)

Abacavir has been used in a triple NRTI regimen that includes abacavir, lamivudine, and zidovudine. The fixed-combination preparation containing these 3 NRTIs (abacavir/lamivudine/zidovudine; Trizivir) can be used in adults and adolescents weighing 40 kg or more. Abacavir/lamivudine/zidovudine is intended only for regimens that require all 3 drugs, and clinicians should consider that data are limited regarding use of this fixed-combination preparation in patients with baseline viral loads exceeding 100,000 copies/mL. Although a triple NRTI regimen of abacavir, lamivudine, and zidovudine offers the advantages of fewer drug interactions, low pill burden, and ease of administration (because of the commercially available fixed-combination preparation), and spares patients from potential adverse effects associated with PIs and NNRTIs, there is a high rate of virologic non-response when the regimen is used in treatment-naive patients. Therefore, experts state that a triple NRTI regimen that includes abacavir, lamivudine, and zidovudine is not recommended for initial therapy in antiretroviral-naive adults and adolescents and should be used only when other regimens cannot be used.

Safety and efficacy of the triple NRTI regimen of abacavir, lamivudine, and zidovudine were evaluated in a randomized, double-blind study (study CNA3005) in 562 HIV-infected, treatment-naive adults (median baseline CD4 T-cell counts 359-360/mm, median baseline plasma HIV-1 RNA levels 4.8-4.9 log10 copies/mL). Patients were randomized to receive a 3-drug regimen of abacavir (300 mg twice daily) and the fixed-combination preparation containing lamivudine and zidovudine (lamivudine/zidovudine; Combivir; 150 mg of lamivudine and 300 mg of zidovudine twice daily) or a 3-drug regimen of indinavir (800 mg every 8 hours), lamivudine (150 mg twice daily), and zidovudine (300 mg twice daily). At week 48, 51% of patients in both treatment groups had plasma HIV-1 RNA levels less than 400 copies/mL and 40% of those receiving abacavir, lamivudine, and zidovudine and 46% of those receiving indinavir, lamivudine, and zidovudine had plasma HIV-1 RNA levels of 50 copies/mL or less (intent-to-treat analysis). In patients with baseline HIV-1 RNA levels exceeding 100,000 copies/mL, a greater proportion of those who received the indinavir-containing regimen (45%) had plasma HIV-1 RNA levels less than 50 copies/mL than those who received the abacavir-containing regimen (31%). The median change in CD4 T-cell count at 48 weeks was similar in both treatment groups.

A triple NRTI regimen of abacavir, lamivudine, and tenofovir disoproxil fumarate (tenofovir DF) is not recommended at any time in antiretroviral-naive or antiretroviral-experienced adults and adolescents because of a high rate of virologic failure. Interim analysis of a randomized, open-label study evaluating efficacy of a once-daily regimen of abacavir, lamivudine, and tenofovir DF compared with an NNRTI-based once-daily regimen of efavirenz, abacavir, and lamivudine in treatment-naive patients (ESS30009) indicated a high rate of early virologic nonresponse in those receiving the triple NRTI regimen (almost 50%). Based on these results, the abacavir, lamivudine, and tenofovir DF arm of the study was terminated. A high rate of virologic nonresponse also was reported in a pilot study evaluating this triple NRTI regimen. Several possible reasons for the poor response to this regimen have been proposed, but the ESS30009 investigators suggest that the most likely cause is a low genetic barrier to resistance because of synergistic selection from all 3 NRTIs for 2 specific resistance mutations (M184V and K65R).

A quadruple NRTI regimen of abacavir, lamivudine, tenofovir DF, and zidovudine is not recommended for initial treatment in antiretroviral-naive HIV-infected adults and adolescents because of inferior virologic efficacy. In an open-label pilot study, a quadruple NRTI regimen was compared with an NNRTI-based regimen of efavirenz with lamivudine and zidovudine, and both regimens had similar efficacy and tolerability. However, a larger, open-label study comparing a similar quadruple NRTI regimen (abacavir, emtricitabine, tenofovir DF, zidovudine) with a standard NNRTI- or PI-based regimen found that substantially fewer patients receiving the quadruple NRTI regimen achieved HIV-1 RNA levels below 200 copies/mL.

Dolutegravir, Abacavir, and Lamivudine

Efficacy and safety of an INSTI-based regimen of dolutegravir and the dual NRTI option of abacavir and lamivudine have been evaluated in a phase 3 randomized, double-blind, active-controlled study (SINGLE) in antiretroviral-naive HIV-1-infected adults. Patients were randomized to receive dolutegravir 50 mg once daily in conjunction with abacavir/lamivudine or the fixed-combination preparation containing efavirenz, emtricitabine, and tenofovir DF (efavirenz/emtricitabine/tenofovir DF) for a 96-week double-blind phase followed by an open-label phase through week 144. Baseline characteristics of the 833 study patients were similar in both treatment groups (median age 35 years, 16% female, 32% non-white, 7% with HCV coinfection, 4% CDC Class C, median plasma HIV-1 RNA level 4.68 log10 copies/mL, median baseline CD4 T-cell count 338 cells/mm). At 144 weeks, 71% of patients receiving dolutegravir with abacavir/lamivudine and 63% of those receiving efavirenz/emtricitabine/tenofovir DF achieved plasma HIV-1 RNA levels less than 50 copies/mL. The adjusted mean increase in CD4 T-cell count was 378 cells/mm in those receiving dolutegravir and abacavir/lamivudine compared with 332 cells/mm in those receiving efavirenz/emtricitabine/tenofovir DF.

Efavirenz, Abacavir, and Lamivudine

Efficacy and safety of an NNRTI-based regimen of efavirenz and the dual NRTI option of abacavir and lamivudine have been evaluated in a randomized, double-blind study (study CNA30024) in 649 HIV-infected, treatment-naive adults (median baseline CD4 T-cell count 264/mm, median baseline plasma HIV-1 RNA level 4.79 log10 copies/mL). Patients were randomized to receive a 3-drug regimen of abacavir (300 mg twice daily), lamivudine (150 mg twice daily), and efavirenz (600 mg once daily) or a 3-drug regimen of zidovudine (300 mg twice daily), lamivudine (150 mg twice daily), and efavirenz (600 mg once daily). At week 48 (intent-to-treat analysis), about 69% of patients in both treatment groups had plasma HIV-1 RNA levels of 50 copies/mL or less. At week 48, the mean increase from baseline CD4 T-cell count was 209/mm in those receiving abacavir, lamivudine, and efavirenz and 155/mm in those receiving zidovudine, lamivudine, and efavirenz.

The comparative efficacy of a once- or twice-daily abacavir regimen used with lamivudine in an NNRTI-based regimen was evaluated in a randomized, double-blind study (study CNA30021) in 770 HIV-infected, treatment-naive adults (median baseline CD4 T-cell count 262/mm and median baseline plasma HIV-1 RNA level 4.89 log10 copies/mL). Patients were randomized to receive a regimen of abacavir (600 mg once daily), lamivudine (300 mg once daily), and efavirenz (600 mg once daily) or abacavir (300 mg twice daily), lamivudine (300 mg once daily), and efavirenz (600 mg once daily). At week 48 (intent-to-treat analysis), 64 or 65% of patients receiving abacavir once or twice daily, respectively, had plasma HIV-1 RNA levels less than 50 copies/mL. At week 48, the mean increase from baseline CD4 T-cell count was 188/mm in those receiving abacavir once daily and 200/mm in those receiving abacavir twice daily.

Efficacy and safety of the fixed combination of abacavir and lamivudine (abacavir/lamivudine) in conjunction with efavirenz were evaluated in a randomized, open-label study (ASSERT study) in 385 HIV-infected, HLA-B*5701-negative, antiretroviral-naive adults (median baseline CD4 T-cell count 240/mm, median baseline plasma HIV-1 RNA level 5.06 log10 copies/mL). Patients were randomized to receive a 96-week NNRTI-based regimen of efavirenz and either abacavir/lamivudine or the fixed combination of emtricitabine and tenofovir DF (emtricitabine/tenofovir DF). At week 48, 59 or 67% of patients receiving abacavir/lamivudine in conjunction with efavirenz had achieved HIV-1 RNA levels below 50 or 400 copies/mL, respectively, compared with 71 or 77%, respectively, of those receiving emtricitabine/tenofovir DF in conjunction with efavirenz. Despite HLA-B*5701 testing to ensure that patients in the study were HLA-B*5701-negative, there were 6 cases of clinically suspected hypersensitivity reactions to abacavir.

PI-based Regimens

PI-based regimens that include the fixed combination of abacavir/lamivudine have been evaluated in an open-label study (KLEAN study) in 887 antiretroviral-naive adults (median baseline HIV-1 RNA level 5.1 log10 copies/mL, median CD4 count 192/mm). Patients were randomized to receive either ritonavir-boosted fosamprenavir (700 mg fosamprenavir twice daily and 100 mg ritonavir twice daily) or lopinavir/ritonavir (400 mg lopinavir/100 mg ritonavir twice daily) each in conjunction with abacavir/lamivudine (600 mg abacavir/300 mg lamivudine once daily). The time to loss of virologic response (TLOVR) analysis of the intent-to-treat exposed population (ITT-E) indicated that the proportion of patients achieving HIV-1 RNA levels less than 50 copies/mL at 48 weeks was similar between the 2 groups: 66% in the group receiving abacavir/lamivudine with ritonavir-boosted fosamprenavir and 65% in the group receiving abacavir/lamivudine with lopinavir/ritonavir. At the time of the 48-week analysis, there had been 32 cases of suspected abacavir hypersensitivity in the group receiving abacavir/lamivudine with ritonavir-boosted fosamprenavir and 21 cases in the group receiving abacavir/lamivudine with lopinavir/ritonavir. A long-term extension of the KLEAN study included 199 patients from the initial study who had plasma HIV-1 RNA levels less than 400 copies/mL at 48 weeks and continued to receive the PI-based regimen (abacavir/lamivudine was replaced with another dual NRTI option in 14 patients, principally because of suspected abacavir hypersensitivity) for a total of 144 weeks. At week 144, TLOVR analysis of the ITT-E extension population indicated that 73% of those receiving ritonavir-boosted fosamprenavir and 60% of those receiving lopinavir/ritonavir had plasma HIV-1 RNA levels less than 50 copies/mL. Both PI-based regimens were well tolerated and had similar safety profiles when used in conjunction with the fixed combination of abacavir/lamivudine over 144 weeks.

The comparative safety and efficacy of PI-based regimens of lopinavir/ritonavir with either the fixed combination of abacavir/lamivudine or the fixed combination of emtricitabine/tenofovir DF were evaluated in a randomized, double-blind, placebo-matched study (HEAT study) in 688 antiretroviral-naive adults (median baseline HIV-1 RNA level 4.9 log10 copies/mL, median CD4 count 202/mm). Patients were randomized to receive lopinavir/ritonavir (800 mg lopinavir/200 mg ritonavir once daily) and the dual NRTI option of abacavir/lamivudine (600 mg abacavir/300 mg lamivudine once daily) with emtricitabine/tenofovir DF placebo or the dual NRTI option of emtricitabine/tenofovir DF (200 mg emtricitabine/300 mg tenofovir DF once daily) with abacavir/lamivudine placebo. At week 48, similar proportions of the ITT-E population receiving the PI with abacavir/lamivudine or emtricitabine/tenofovir DF achieved HIV-1 RNA levels less than 50 copies/mL (68 or 67%, respectively). At week 96, 60 or 58% of the ITT-E population receiving the PI with abacavir/lamivudine or emtricitabine/tenofovir DF, respectively, maintained HIV-1 RNA levels less than 50 copies/mL. The median increase from baseline CD4 T-cell count at week 96 in both groups also was similar (250 or 247 cells/mm, respectively). Both regimens were well tolerated and had similar rates of treatment discontinuance (6%).

Data regarding efficacy of a dual NRTI option of abacavir/lamivudine fixed combination compared with that of emtricitabine/tenofovir DF fixed combination were obtained from a randomized, double-blind study in antiretroviral-naive adults that involved a PI-based regimen including open-label ritonavir-boosted atazanavir or an NNRTI-based regimen including open-label efavirenz (ACTG study A5202). Patients were stratified by baseline HIV-1 RNA levels (less than 100,000 copies/mL or 100,000 copies/mL or greater). Results of an interim analysis after a median 60 weeks of therapy indicated that patients with baseline HIV-1 RNA levels 100,000 copies/mL or greater receiving the dual NRTI option of abacavir/lamivudine had substantially shorter times to virologic failure compared with those receiving tenofovir DF/emtricitabine.

Antiretroviral-experienced Adults and Adolescents

All-NRTI Regimens

Abacavir has been used in triple NRTI regimens in antiretroviral-experienced HIV-infected adults and adolescents, but triple NRTI regimens usually are not recommended because of inferior virologic efficacy or lack of data.

A triple NRTI regimen that includes abacavir (300 mg twice daily) and the fixed-combination preparation containing lamivudine and zidovudine (lamivudine/zidovudine; Combivir; 150 mg of lamivudine and 300 mg of zidovudine twice daily) has been evaluated in a 48-week, open-label study in HIV-infected patients who previously received antiretroviral regimens that included 1 or 2 NRTIs without any other antiretroviral agents. At the start of the study, 34% of patients had baseline plasma HIV-1 RNA levels less than 400 copies/mL and 11% had levels less than 50 copies/mL; the median CD4 T-cell count was 506/mm. At 48 weeks, 82% of patients had plasma HIV-1 RNA levels less than 400 copies/mL and 56% had levels less than 50 copies/mL (intent-to-treat analysis). Patients with baseline HIV-1 RNA levels less than 5000 copies/mL were more likely to achieve levels less than 400 copies/mL at week 48 than those with baseline levels exceeding 5000 copies/mL. At 48 weeks, the median change from baseline CD4 T-cell count was 66 cells/mm. While triple NRTI regimens generally are not recommended, some experts state that a regimen of the fixed combination of abacavir, lamivudine, and zidovudine (abacavir/lamivudine/zidovudine) may be considered in patients when other regimens cannot be used.

Based on interim analysis of a study evaluating a triple NRTI regimen of abacavir, lamivudine, and tenofovir DF that indicated a high rate of early virologic nonresponse in treatment-naive patients receiving this regimen, a triple NRTI regimen of abacavir, lamivudine, and tenofovir DF is not recommended at any time in either antiretroviral-naive or antiretroviral-experienced patients.

In a study in 460 patients receiving a PI and 2 NRTIs who had maintained plasma HIV-1 RNA levels less than 200 copies/mL for at least 6 months but wished to change to a regimen that did not include a PI, patients were randomized to switch from their existing PI to abacavir, efavirenz, or nevirapine while maintaining the existing NRTIs. At 12 months, 13, 6, or 10% of patients switched to abacavir, efavirenz, or nevirapine, respectively, had experienced death, progression to acquired immunodeficiency syndrome (AIDS), or an increase in plasma HIV-1 RNA levels to 200 copies/mL or more (intent-to-treat analysis).

Dolutegravir, Abacavir, and Lamivudine

The comparative efficacy and safety of dolutegravir in conjunction with an investigator-selected optimized background antiretroviral regimen (OBR), including an OBR of abacavir in fixed combination with lamivudine (abacavir/lamivudine) in a limited number of patients, are being studied in 715 antiretroviral-experienced, INSTI-naive HIV-1-infected adults in an ongoing phase 3, randomized, double-blind, active-controlled, double-placebo study (SAILING). All enrolled patients had previously received antiretroviral therapy (average duration 77 months of prior therapy) and had infections resistant to at least 2 classes of antiretrovirals (49% had HIV-1 resistant to at least 3 classes of antiretrovirals). Patients were randomized to receive dolutegravir 50 mg once daily or raltegravir 400 mg twice daily, each in conjunction with an OBR consisting of at least 1 fully active antiretroviral; of those in the dolutegravir group, 8 patients received an OBR of abacavir/lamivudine. Baseline characteristics were similar in both treatment groups (median age 43 years, 32% female, 50% non-white, 16% with HBV and/or HCV coinfection, 46% CDC Class C, 20% with plasma HIV-1 RNA levels greater than 100,000 copies/mL, 72% with CD4 T-cell counts less than 350 cells/mm). At 48 weeks, 71% of patients in the dolutegravir group and 64% of those in the raltegravir group had plasma HIV-1 RNA levels less than 50 copies/mL; CD4 T-cell counts were increased from baseline in both groups (mean change 162 cells/mm in the dolutegravir group and 153 cells/mm in the raltegravir group).

Pediatric Patients

Abacavir is used in conjunction with other antiretroviral agents for treatment of HIV-1 infection in pediatric patients 3 months of age or older.

Abacavir/lamivudine is used in conjunction with other antiretrovirals for the treatment of HIV-1 infection in pediatric patients weighing 25 kg or more.

Abacavir/lamivudine/zidovudine is used for the treatment of HIV-1 infection in pediatric patients weighing 40 kg or more.

For initial treatment of HIV-infected pediatric patients, the HHS Panel on Antiretroviral Therapy and Medical Management of HIV-infected Children recommends a regimen that includes a ritonavir-boosted PI, NNRTI, or INSTI in conjunction with 2 NRTIs (dual NRTIs). These experts state that abacavir and lamivudine (or emtricitabine) is a preferred dual NRTI option and abacavir and zidovudine is an alternative dual NRTI option for use in PI-, NNRTI-, or INSTI-based regimens for initial treatment in antiretroviral-naive children 3 months of age or older who are HLA-B*5701 negative.

The dual NRTI options of abacavir and didanosine or abacavir and tenofovir DF are not recommended for use in initial antiretroviral regimens in antiretroviral-naive pediatric patients because of insufficient data.

Antiretroviral regimens that contain only NRTIs are not recommended for initial treatment in antiretroviral-naive children because of inferior virologic efficacy.

A triple NRTI regimen that includes abacavir, tenofovir DF, and either lamivudine or emtricitabine should not be used at any time in pediatric patients because of the high rate of early virologic failure reported in antiretroviral-naive adults.(See All-NRTI Regimens under Treatment of HIV Infections: Pediatric Patients, in Uses.)

For further information on treatment of HIV infection in pediatric patients,

All-NRTI Regimens

Efficacy of a triple NRTI regimen of abacavir, lamivudine, and zidovudine in pediatric patients has been evaluated in a phase 3, randomized, double-blind study (study CNA3006) that included 205 HIV-infected children 3 months to 13 years of age (median age: 5.4 years, 56% female, 17% white, 50% African American, 30% Hispanic, median baseline CD4 T-cell percentage 27%, median baseline plasma HIV-1 RNA levels 4.6 log10 copies/mL); more than 50% had previously received NRTI therapy for longer than 2 years. Children were randomized to receive a 3-drug regimen of abacavir (8 mg/kg twice daily), lamivudine (4 mg/kg twice daily), and zidovudine (180 mg/m twice daily) or a 2-drug regimen of lamivudine (4 mg/kg twice daily) and zidovudine (180 mg/m twice daily). At week 16, the median CD4 T-cell count increase from baseline was 69 or 9/mm in those receiving the 3- or 2-drug regimen, respectively. At week 48, 17 or 2% of those receiving the 3- or 2-drug regimen, respectively, had plasma HIV-1 RNA levels of 400 copies/mL or less (as-treated analysis). The median decrease from baseline in plasma HIV-1 RNA was twofold to threefold greater in those receiving the 3-drug regimen than in those receiving the 2-drug regimen.

There is evidence from a limited study in HIV-infected children that a triple NRTI regimen of abacavir, lamivudine, and zidovudine can reduce CSF viral load. HIV-infected children who previously had received antiretroviral agent therapy were randomized to a 3-drug regimen of abacavir, lamivudine, and zidovudine or a 2-drug regimen of lamivudine and zidovudine, and baseline CSF HIV-1 RNA levels were determined. At week 16, 69% of those receiving the 3-drug regimen and 70% of those receiving the 2-drug regimen had undetectable CSF HIV-1 RNA (less than 100 copies/mL).

PI-based Regimens

Initial evidence from limited studies in treatment-naive pediatric patients 3 months to 13 years of age indicated that a 3-drug regimen that included 2 NRTIs (abacavir, lamivudine, or zidovudine) and nelfinavir can decrease plasma HIV-1 RNA levels to less than 400 copies/mL and substantially increase CD4 T-cells in these patients.

The comparative efficacy of 3 different NRTI options was evaluated in 128 antiretroviral-naive HIV-infected pediatric patients 3 months to 16 years of age (median age 5.4 years, median baseline CD4 percentage 22%, mean baseline HIV-1 RNA 5.1 log10 copies/mL) who were randomized to receive open-label dual NRTI options of abacavir and lamivudine, abacavir and zidovudine, or zidovudine and lamivudine with or without nelfinavir (Penta 5 study). Asymptomatic patients (n=55) were randomized to receive nelfinavir or placebo, while patients with more advanced HIV disease received open-label nelfinavir. At 48 weeks, intent-to-treat analysis indicated that reductions in plasma HIV-1 RNA levels were greater in children receiving an abacavir-containing dual NRTI option (decrease of 2.19 log10 copies/mL with abacavir and zidovudine or 2.63 log10 copies/mL with abacavir and lamivudine) than in those receiving the option containing zidovudine and lamivudine (decrease of 1.71 log10 copies/mL). At 5 years (intent-to-treat analysis in patients randomized to receive nelfinavir), plasma HIV-1 RNA levels were less than 50 copies/mL in 69% of those randomized to receive abacavir and lamivudine compared with 26 or 33% of those randomized to receive abacavir and zidovudine or zidovudine and lamivudine, respectively.

Once-daily versus Twice-daily Regimens

Efficacy and safety of abacavir and lamivudine in conjunction with other antiretrovirals were evaluated in a randomized, open-label, parallel-group study in 1206 HIV-1-infected treatment-naive infants, children, and adolescents 3 months to 17 years of age (ARROW). After a minimum of 36 weeks of treatment with a first-line regimen containing the dual NRTI option of abacavir and lamivudine (administered twice daily) in conjunction with a ritonavir-boosted PI or NNRTI, the comparative efficacy of a once- or twice-daily regimen of abacavir and lamivudine in conjunction with other antiretrovirals was evaluated in 669 patients weighing at least 25 kg (median age 5.5 years, 52% female, median time on twice-daily abacavir and lamivudine regimen 1.8 years). Patients were randomized in a 1:1 ratio to receive a once- or twice-daily regimen of abacavir and lamivudine (given as single-entity preparations or as abacavir/lamivudine) in conjunction with other antiretrovirals. At the time of randomization, 71% of those in the once-daily group and 75% of those in the twice-daily group were virologically suppressed. At 96 weeks, 67% of those receiving a once-daily regimen and 70% of those receiving a twice-daily regimen of abacavir and lamivudine achieved HIV-1 RNA levels less than 80 copies/mL.

Postexposure Prophylaxis following Occupational Exposure to HIV

Abacavir is used in conjunction with other antiretroviral agents for postexposure prophylaxis of HIV infection following occupational exposure (PEP) in health-care personnel and other individuals exposed via percutaneous injury (e.g., needlestick, cut with sharp object) or mucous membrane or nonintact skin (e.g., chapped, abraded, dermatitis) contact with blood, tissue, or other body fluids that might contain HIV.

The US Public Health Service (USPHS) states that the preferred regimen for PEP following an occupational exposure to HIV is a 3-drug regimen of raltegravir used in conjunction with emtricitabine and tenofovir DF (may be administered as the fixed combination emtricitabine/tenofovir DF; Truvada). These experts state that abacavir is one of several alternative agents that may be used in PEP regimens, but should be used for PEP only with expert consultation since HLA-B*5701 testing is required and such testing may not be available or practical prior to initiating PEP.

Because management of occupational exposures to HIV is complex and evolving, consultation with an infectious disease specialist, clinician with expertise in administration of antiretroviral agents, and/or the National Clinicians' Postexposure Prophylaxis Hotline (PEPline at 888-448-4911) is recommended whenever possible. However, initiation of PEP should not be delayed while waiting for expert consultation.

For information on types of occupational exposure to HIV and associated risk of infection, management of occupational exposure to HIV, efficacy and safety of postexposure prophylaxis, and recommendations regarding PEP,

Postexposure Prophylaxis following Nonoccupational Exposure to HIV

Antiretrovirals are used for postexposure prophylaxis of HIV infection following nonoccupational exposure (nPEP) in individuals exposed to blood, genital secretions, or other potentially infectious body fluids that might contain HIV when the exposure represents a substantial risk for HIV transmission.

When nPEP is indicated following a nonoccupational exposure to HIV, the US Centers for Disease Control and Prevention (CDC) states that the preferred regimen in adults and adolescents 13 years of age or older with normal renal function is either raltegravir or dolutegravir used in conjunction with emtricitabine and tenofovir DF (administered as emtricitabine/tenofovir DF; Truvada); the recommended alternative nPEP regimen in these patients is ritonavir-boosted darunavir used in conjunction with emtricitabine/tenofovir DF.

CDC states that abacavir should not be used in any nPEP regimens since the need for prompt initiation of nPEP does not allow time for HLA-B*5701 screening.

Consultation with an infectious disease specialist, clinician with expertise in administration of antiretroviral agents, and/or the National Clinicians' Postexposure Prophylaxis Hotline (PEPline at 888-448-4911) is recommended if nPEP is indicated in certain exposed individuals (e.g., pregnant women, children, those with medical conditions such as renal impairment) or if an antiretroviral regimen not included in the CDC guidelines is being considered, the source virus is known or likely to be resistant to antiretrovirals, or the healthcare provider is inexperienced in prescribing antiretrovirals. However, initiation of nPEP should not be delayed while waiting for expert consultation.

For additional information on nonoccupational exposure to HIV and recommendations regarding postexposure prophylaxis,

Dosage and Administration

Administration

Abacavir sulfate is administered orally once or twice daily without regard to meals.

Single-entity abacavir sulfate is commercially available as an oral solution or tablets. Abacavir sulfate also is commercially available in fixed combination with other antiretrovirals.(See Fixed Combinations Containing Abacavir under Dosage and Administration: Administration.)

Abacavir is used in conjunction with other antiretrovirals. Single-entity abacavir should not be used concomitantly with any other abacavir-containing preparation.

Abacavir oral solution is used in pediatric patients or when a solid oral dosage form is inappropriate.

The scored 300-mg abacavir tablets are used in adults and may be used in children weighing 14 kg or greater who have undergone assessment demonstrating ability to reliably swallow tablets.

All patients should be screened for the human leukocyte antigen (HLA)-B*5701 allele before abacavir or a fixed-combination preparation containing abacavir is initiated or reinitiated, unless there is documentation of previous HLA-B*5701 allele assessment. Abacavir and abacavir-containing preparations are contraindicated in HLA-B*5701-positive individuals.(See Cautions: Hypersensitivity Reactions.)

Fixed Combinations Containing Abacavir

Abacavir sulfate is commercially available in fixed-combination tablets containing abacavir and lamivudine (abacavir/lamivudine; Epzicom), in fixed-combination tablets containing abacavir, dolutegravir, and lamivudine (abacavir/dolutegravir/lamivudine; Triumeq), and in fixed-combination tablets containing abacavir, lamivudine, and zidovudine (abacavir/lamivudine/zidovudine; Trizivir).

Abacavir/lamivudine (Epzicom) tablets are administered orally once daily without regard to meals. A fixed-combination tablet containing 600 mg of abacavir and 300 mg of lamivudine is bioequivalent to two 300-mg tablets of abacavir and two 150-mg tablets of lamivudine given simultaneously. For the treatment of human immunodeficiency virus type 1 (HIV-1) infection, abacavir/lamivudine is used in conjunction with other antiretrovirals.

Abacavir/dolutegravir/lamivudine (Triumeq) film-coated tablets are administered orally once daily without regard to food. A fixed-combination tablet containing 600 mg of abacavir, 50 mg of dolutegravir, and 300 mg of lamivudine is bioequivalent to a 50-mg tablet of dolutegravir administered simultaneously with a fixed-combination tablet containing 600 mg of abacavir and 300 mg of lamivudine. For the treatment of HIV-1 infection, abacavir/dolutegravir/lamivudine is used alone as a complete treatment regimen or in conjunction with other antiretrovirals.

Abacavir/lamivudine/zidovudine (Trizivir) tablets are administered orally twice daily without regard to meals. A fixed-combination tablet containing 300 mg of abacavir, 150 mg of lamivudine, and 300 mg of zidovudine is bioequivalent to a 300-mg tablet of abacavir, a 150-mg tablet of lamivudine, and a 300-mg tablet of zidovudine administered simultaneously. For the treatment of human HIV-1 infection, abacavir/lamivudine/zidovudine is used alone as a complete treatment regimen or in conjunction with other antiretrovirals.

Because the antiretroviral agents contained in abacavir/lamivudine, abacavir/dolutegravir/lamivudine, and abacavir/lamivudine/zidovudine also are commercially available in single-entity or other fixed-combination preparations, care should be taken to ensure that therapy is not duplicated when a fixed combination is used in conjunction with other antiretrovirals.(See Precautions Related to Use of Fixed Combinations under Cautions: Precautions and Contraindications.)

Dosage

Abacavir is commercially available as abacavir sulfate; dosage is expressed in terms of abacavir.

Adult Dosage

Treatment of HIV Infection

The usual dosage of abacavir (Ziagen) for the treatment of HIV-1 infection in adults is 600 mg once daily or 300 mg twice daily.

When abacavir/lamivudine (Epzicom) is used for the treatment of HIV-1 infection, adults should receive 1 tablet (600 mg of abacavir and 300 mg of lamivudine) once daily.

When abacavir/dolutegravir/lamivudine (Triumeq) is used for the treatment of HIV-1 infection, adults should receive 1 tablet (600 mg of abacavir, 50 mg of dolutegravir, and 300 mg of lamivudine) once daily.

When abacavir/lamivudine/zidovudine (Trizivir) is used for the treatment of HIV-1 infection, adults should receive 1 tablet (300 mg of abacavir, 150 mg of lamivudine, and 300 mg of zidovudine) twice daily.

Postexposure Prophylaxis following Occupational Exposure to HIV

For postexposure prophylaxis of HIV infection following occupational exposure (PEP) in health-care personnel or other individuals, abacavir is administered in a dosage of 600 mg once daily in conjunction with other antiretrovirals.(See Uses: Postexposure Prophylaxis following Occupational Exposure to HIV.)

The PEP regimen should be initiated as soon as possible following occupational exposure to HIV (preferably within hours) and continued for 4 weeks, if tolerated.

Pediatric Dosage

Treatment of HIV Infection

The usual dosage of abacavir oral solution (Ziagen) for the treatment of HIV-1 infection in children and adolescents 3 months of age and older is 8 mg/kg (up to 300 mg) twice daily or 16 mg/kg (up to 600 mg) once daily. When the abacavir oral suspension is used for initial antiretroviral therapy in pediatric patients, some experts recommend that a twice-daily regimen be used initially and, based on response, consideration can then be given to switching to a once-daily regimen after approximately 24 weeks of therapy.

In pediatric patients 3 months of age or older weighing 14 kg or more who can reliably swallow tablets, the usual dosage of abacavir tablets (Ziagen) for the treatment of HIV-1 infection is based on weight. (See Table 1 and Table 2.) Although a once- or twice-daily regimen of abacavir tablets can be used in pediatric patients, some experts recommend that a once-daily regimen be used.

Table 1. Twice-daily Regimen in Children and Adolescents Weighing >=14 kg Able to Swallow Tablets (Ziagen® 300-mg Tablets)[1 ]
Weight (kg) AM Dose PM Dose
14 to <20 150 mg (half tablet) 150 mg (half tablet)
20 to <25 150 mg (half tablet) 300 mg
>=25 300 mg 300 mg
Table 2. Once-daily Regimen in Children and Adolescents Weighing >=14 kg Able to Swallow Tablets (Ziagen® 300-mg Tablets)[1 ]
Weight (kg) Once-daily Dose
14 to <20 300 mg
20 to <25 450 mg (one and one-half tablets)
>=25 600 mg (2 tablets)

When abacavir/lamivudine (Epzicom) is used for the treatment of HIV-1 infection, children and adolescents weighing at least 25 kg should receive 1 tablet (600 mg of abacavir and 300 mg of lamivudine) once daily.

When abacavir/lamivudine/zidovudine (Trizivir) is used for the treatment of HIV-1 infection, pediatric patients weighing 40 kg or more should receive 1 tablet (300 mg of abacavir, 150 mg of lamivudine, and 300 mg of zidovudine) twice daily.

Safety and efficacy of abacavir/dolutegravir/lamivudine (Triumeq) have not been established in pediatric patients.

Dosage in Renal and Hepatic Impairment

Renal Impairment

Only limited information is available on the pharmacokinetics of abacavir in patients with impaired renal function, and the manufacturer provides no guidance on abacavir dosage adjustment in such patients. Some experts state that the usual dosage of abacavir can be used in adults and adolescents with impaired renal function.

Abacavir/lamivudine, abacavir/dolutegravir/lamivudine, and abacavir/lamivudine/zidovudine are not recommended in patients with creatinine clearance less than 50 mL/minute.

Hepatic Impairment

If abacavir (Ziagen) is used in adults with mild hepatic impairment (Child-Pugh score 5-6), the manufacturer recommends that dosage of the drug for treatment of HIV-1 infection be reduced to 200 mg twice daily. To facilitate this dosage adjustment in these patients, the commercially available oral solution should be used (i.e., 10 mL twice daily). Abacavir is contraindicated in patients with moderate or severe hepatic impairment since safety, efficacy, and pharmacokinetics have not been established in these patients.

Abacavir/lamivudine, abacavir/dolutegravir/lamivudine, and abacavir/lamivudine/zidovudine are not recommended in patients with mild hepatic impairment and are contraindicated in those with moderate or severe hepatic impairment.

Cautions

Information on safety and efficacy of abacavir has been obtained principally from initial clinical studies in adult and pediatric patients with human immunodeficiency virus (HIV) infection who received the recommended dosage of the drug in conjunction with other antiretrovirals (e.g., lamivudine, zidovudine, efavirenz).

Although abacavir generally is well tolerated, potentially life-threatening hypersensitivity reactions have been reported in patients receiving the drug.(See Cautions: Hypersensitivity Reactions.)

When the fixed combination containing abacavir and lamivudine (abacavir/lamivudine), fixed combination containing abacavir, dolutegravir, and lamivudine (abacavir/dolutegravir/lamivudine), or fixed combination containing abacavir, lamivudine, and zidovudine (abacavir/lamivudine/zidovudine) is used, the adverse effects, precautions, and contraindications associated with each drug in the fixed combination should be considered.(See Precautions Related to Use of Fixed Combinations under Cautions: Precautions and Contraindications.)

Hypersensitivity Reactions

Serious, sometimes fatal, hypersensitivity reactions have been reported with abacavir or fixed-combination preparations containing abacavir (abacavir/lamivudine, abacavir/lamivudine/zidovudine). In clinical studies, hypersensitivity reactions have been reported in approximately 8% of patients receiving abacavir in conjunction with other antiretrovirals. In one controlled study (CNA30021), the incidence of severe hypersensitivity reactions was greater in adults receiving abacavir once daily (5%) than in those receiving abacavir twice daily (2%).

There is evidence that abacavir hypersensitivity is an immunologic reaction influenced by certain genetic factors. An association between presence of the human leukocyte antigen (HLA)-B*5701 allele and abacavir hypersensitivity has been established. Individuals who carry the HLA-B*5701 allele are at higher risk for abacavir hypersensitivity reactions, although hypersensitivity reactions have occurred in patients who do not carry the HLA-B*5701 allele.

Manifestations of hypersensitivity usually are apparent within the first 6 weeks of abacavir therapy (median time to onset is 9 days), but may occur at any time during therapy. Severe hypersensitivity reactions can occur within hours following rechallenge in patients with a prior history of hypersensitivity to the drug, and these reactions may include life-threatening hypotension and death. The most severe hypersensitivity reactions reported to date have been in individuals who were rechallenged with abacavir after a previous hypersensitivity reaction to the drug. There also have been reports of severe or fatal hypersensitivity reactions occurring after abacavir was reintroduced in patients with no identified history of abacavir hypersensitivity or with unrecognized manifestations of hypersensitivity to the drug. Although these patients had discontinued abacavir for reasons unrelated to hypersensitivity (e.g., interruption in drug supply, discontinuance of abacavir during treatment for other medical conditions), some may have had symptoms present before discontinuance of the drug that were consistent with hypersensitivity but were attributed to other medical conditions (e.g., acute onset respiratory disease, gastroenteritis, adverse reactions to other drugs). Most of the hypersensitivity reactions reported following reintroduction of abacavir in these patients were indistinguishable from hypersensitivity reactions associated with abacavir rechallenge (i.e., short time to onset, increased severity of symptoms, poor outcome including death). Hypersensitivity reactions can occur within hours after abacavir is reintroduced; however, in some cases, these reactions occurred days to weeks following reintroduction of the drug.

Hypersensitivity reactions reported in patients receiving abacavir are characterized by the appearance of manifestations indicating involvement of multiple organ and body systems; these reactions have occurred in association with anaphylaxis, liver failure, renal failure, hypotension, and death. The most frequent manifestations of abacavir hypersensitivity include signs or symptoms from at least 2 of the following groups: fever, rash, GI symptoms (including nausea, vomiting, diarrhea, abdominal pain), constitutional symptoms (including generalized malaise, fatigue, achiness), and respiratory symptoms (including pharyngitis, dyspnea, cough). Other signs and symptoms include lethargy, myalgia, chills, myolysis, headache, arthralgia, edema, tachycardia, abnormal chest radiographs (predominantly infiltrates, which may be localized), paresthesia, lymphadenopathy, and mucous membrane lesions (e.g., conjunctivitis, mouth ulceration). Respiratory symptoms, including cough, dyspnea, and pharyngitis, have been reported in approximately 20% of patients with hypersensitivity reactions to abacavir. Adult respiratory distress syndrome and respiratory failure have occurred in association with hypersensitivity reactions. Some patients who experienced fatal hypersensitivity reactions were initially diagnosed as having an acute respiratory disease (pneumonia, bronchitis, flu-like illness). Hypersensitivity reactions can occur without rash; if rash occurs, it usually is maculopapular or urticarial, but may be variable in appearance. Erythema multiforme has been reported. Laboratory abnormalities reported in patients experiencing a hypersensitivity reaction to abacavir include lymphopenia and increases in serum concentrations of liver enzymes, creatine kinase (CK, creatine phosphokinase, CPK), or creatinine.

Abacavir or fixed-combination preparations containing abacavir should be discontinued immediately in any individual who develops signs or symptoms suggesting hypersensitivity, regardless of HLA-B*5701 status and even when other diagnoses are possible. Clinical status, including liver function tests, should be monitored and appropriate therapy should be initiated. At least one fatality occurred in a patient who continued abacavir therapy despite experiencing a severe hypersensitivity reaction. Symptoms and laboratory abnormalities associated with abacavir hypersensitivity generally resolve following discontinuance of the drug. Abacavir and abacavir-containing preparations should never be reinitiated in any patient who experienced a hypersensitivity reaction while receiving the drug, regardless of the patient's HLA-B*5701 status; more severe symptoms may occur within hours and may include life-threatening hypotension and death. Similar severe reactions have also occurred rarely following the reintroduction of abacavir or abacavir-containing preparations in patients who have no history of abacavir hypersensitivity.(See Precautions Related to Hypersensitivity Reactions under Cautions: Precautions and Contraindications.)

Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported during postmarketing experience in patients receiving abacavir concomitantly with other drugs known to be associated with these severe adverse effects. In such cases, abacavir should be discontinued and should not be reinitiated because of the possibility that the patient may have multiple drug sensitivities and because the clinical signs and symptoms of Stevens-Johnson syndrome and toxic epidermal necrolysis are similar to those of abacavir hypersensitivity. Erythema multiforme has been reported with use of abacavir.

Hepatic Effects and Lactic Acidosis

Lactic acidosis and severe hepatomegaly with steatosis, including some fatalities, have been reported rarely in patients receiving abacavir or fixed-combination preparations containing abacavir (abacavir/lamivudine, abacavir/dolutegravir/lamivudine, abacavir/lamivudine/zidovudine) and have also been reported in patients receiving other HIV nucleoside reverse transcriptase inhibitors (NRTIs). Most reported cases have involved women; obesity and long-term therapy with an NRTI also may be risk factors. Cases also have been reported in patients with no known risk factors.

GI Effects

Adverse GI effects have been reported in patients receiving abacavir. In adults receiving abacavir in conjunction with the fixed-combination preparation of lamivudine and zidovudine (lamivudine/zidovudine; Combivir) in study CNA3005, nausea occurred in 19%, nausea and vomiting occurred in 10%, and diarrhea occurred in 7% of patients. In adults receiving abacavir in conjunction with lamivudine and efavirenz in study CNA30024, nausea, diarrhea, abdominal pain, gastritis, or other GI symptoms occurred in 6-7% and vomiting occurred in 2% of patients.

In one controlled study (CNA30021) evaluating once- or twice-daily abacavir in conjunction with lamivudine and efavirenz, the incidence of severe diarrhea was greater in those receiving abacavir once daily (2%) than in those receiving abacavir twice daily (0%).

In study CNA3006 in HIV-infected children 3 months to 13 years of age, nausea and vomiting occurred in 9% of those receiving abacavir in conjunction with lamivudine and zidovudine and in 2% of those receiving lamivudine and zidovudine without abacavir.

Cardiovascular Effects

Myocardial infarction (MI) has been reported in some patients receiving abacavir.

In July 2008, analysis of data from a large observational study (D:A:D) evaluating short-term and long-term antiretroviral adverse effects in more than 33,000 HIV-infected patients indicated a possible increased risk of MI in patients with current or recent (within the previous 6 months) abacavir therapy. Based on this information, the FDA initiated a safety review of abacavir to assess the possible risk of MI. Studies have reported conflicting results regarding the possible association between the drug and MI risk. Several observational studies and a randomized controlled trial identified increased risk, while other randomized controlled trials and the manufacturer's safety database have not identified such a risk. In response, FDA conducted a meta-analysis of 26 randomized clinical trials that evaluated use of abacavir in adults. This meta-analysis did not identify an increased risk of MI in patients receiving abacavir. While clinicians should be aware of the conflicting data, the FDA recommends that clinicians continue to prescribe abacavir according to approved labeling and that patients not discontinue abacavir without consulting their clinician.

Although the clinical importance has not been determined, myocardial degeneration was found in mice and rats following administration of abacavir for 2 years (systemic exposure equivalent to 7-24 times the expected systemic exposure in humans).

Adipogenic Effects

Redistribution or accumulation of body fat, including central obesity, dorsocervical fat enlargement (''buffalo hump''), peripheral wasting, facial wasting, breast enlargement, and general cushingoid appearance, has been reported in patients receiving antiretroviral agents. The mechanisms responsible for these adipogenic effects and the long-term consequences of these effects are unknown. A causal relationship has not been established.

Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in HIV-infected patients receiving multiple-drug antiretroviral therapy, including abacavir. During the initial phase of treatment, HIV-infected patients whose immune systems respond to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections (e.g., Mycobacterium avium complex [MAC], M. tuberculosis, cytomegalovirus [CMV], Pneumocystis jirovecii [formerly P. carinii]); such responses may necessitate further evaluation and treatment.

Autoimmune disorders (e.g., Graves' disease, polymyositis, Guillain-Barre syndrome) also have been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable and can occur many months after initiation of antiretroviral therapy.

Other Adverse Effects

Headache, malaise and/or fatigue, sleep disorder, or anxiety have occurred in up to 13, 12, 10, or 5% of adults receiving abacavir in conjunction with other antiretroviral agents in clinical studies. Depressive disorders, dizziness, and musculoskeletal pain each have occurred in 6% of adults receiving abacavir in these studies.

Upper respiratory tract infections have been reported in 5% and bronchitis has been reported in 4% of adults receiving abacavir in clinical studies. Fever and/or chills, upper respiratory tract infections, pneumonia, and headache occurred in 9, 5, 4, and 1% of pediatric patients receiving abacavir in clinical studies.

The incidence of laboratory abnormalities (e.g., anemia, neutropenia, liver function test abnormalities, increases in CPK) reported in studies CNA30024, CNA3005, and CNA3006 in adults and children receiving a regimen that includes abacavir was similar to that reported in adults and children receiving regimens without abacavir.

Pancreatitis has been reported rarely in patients receiving abacavir.

Other adverse effects reported during postmarketing experience in patients receiving fixed-combination preparations containing abacavir (abacavir/lamivudine, abacavir/lamivudine/zidovudine) include stomatitis, hyperglycemia, weakness, lymphadenopathy, splenomegaly, posttreatment exacerbation of hepatitis B virus (HBV) infection, muscle weakness, rhabdomyolysis, paresthesia, peripheral neuropathy, seizures, abnormal breath sounds, wheezing, and alopecia. Cardiomyopathy, gynecomastia, anorexia, oral mucosal pigmentation, vasculitis, thrombocytopenia, and increased bilirubin concentrations also have been reported in patients receiving abacavir/lamivudine/zidovudine.

Precautions and Contraindications

Abacavir and fixed combinations containing abacavir (abacavir/lamivudine, abacavir/dolutegravir/lamivudine, abacavir/lamivudine/zidovudine) are contraindicated in patients who have the HLA-B*5701 allele and in patients who have had a previous hypersensitivity reaction to abacavir or any ingredient in the formulation. Abacavir and abacavir-containing preparations should not be reinitiated in any patient who experienced an abacavir hypersensitivity reaction, regardless of the patient's HLA-B*5701 status.(See Precautions Related to Hypersensitivity Reactions under Cautions: Precautions and Contraindications.)

Abacavir, abacavir/lamivudine, abacavir/dolutegravir/lamivudine, and abacavir/lamivudine/zidovudine are contraindicated in patients with moderate or severe hepatic impairment.(See Other Precautions under Cautions: Precautions and Contraindications.) In addition, abacavir/dolutegravir/lamivudine is contraindicated in patients receiving dofetilide.

Precautions Related to Hypersensitivity Reactions

Serious and sometimes fatal hypersensitivity reactions, with multiorgan involvement, have occurred in patients receiving abacavir or fixed-combination preparations containing abacavir.(See Cautions: Hypersensitivity Reactions.)

Prior to initiation or reinitiation of abacavir or a fixed-combination preparation containing abacavir, all patients should be screened for the HLA-B*5701 allele, unless there is documentation of a previous HLA-B*5701 allele assessment. The patient's medical history also should be reviewed for prior exposure to any abacavir-containing preparation. Abacavir and abacavir-containing preparations are contraindicated in individuals who test positive for HLA-B*5701. Such individuals are at higher risk for a hypersensitivity reaction; however, hypersensitivity reactions have occurred in patients who do not carry the HLA-B*5701 allele.

Prospective screening for the HLA-B*5701 allele should not be considered a substitute for close clinical observation and prompt identification and management of abacavir hypersensitivity whenever such reactions occur. A negative test result for HLA-B*5701 does not absolutely rule out the possibility of some form of hypersensitivity reaction. Although abacavir skin patch testing is used as a research tool, such testing should not be used in the clinical diagnosis of abacavir hypersensitivity.

Abacavir and abacavir-containing preparations should be discontinued immediately if a hypersensitivity reaction is suspected, regardless of HLA-B*5701 status and even when other diagnoses are possible (e.g., acute-onset respiratory diseases such as pneumonia, bronchitis, pharyngitis, or influenza; gastroenteritis; reactions to other drugs). Signs or symptoms of hypersensitivity include fever; rash; constitutional symptoms such as malaise, fatigue, achiness; GI symptoms such as nausea, vomiting, diarrhea, or abdominal pain; and respiratory symptoms such as pharyngitis, dyspnea, or cough. Because fatalities have been reported in patients who developed hypersensitivity reactions in which the initial presentation included respiratory symptoms, the diagnosis of hypersensitivity reaction should be carefully considered in any patient receiving abacavir who presents with symptoms of acute-onset respiratory disease, even if alternative respiratory diagnoses (pneumonia, bronchitis, pharyngitis, flu-like illness) are possible.

Abacavir and fixed-combination preparations containing abacavir should never be reinitiated in any patient who experienced a hypersensitivity reaction to abacavir, regardless of the patient's HLA-B*5701 status, since more severe symptoms may recur within hours and may include life-threatening hypotension and death. To minimize the risk of life-threatening hypersensitivity reactions, abacavir should be permanently discontinued if abacavir hypersensitivity cannot be ruled out (regardless of HLA-B*5701 allele status), even when other diagnoses are possible (e.g., acute-onset respiratory diseases, gastroenteritis, adverse reactions to other drugs). If hypersensitivity is ruled out, the manufacturer states that abacavir or other abacavir-containing preparations may be reinitiated, but only if medical care is readily accessible. Rarely, patients who discontinued abacavir for reasons other than hypersensitivity symptoms have experienced life-threatening reactions within hours of reinitiating abacavir.

Patients receiving abacavir or a fixed combination containing abacavir must be fully informed of the signs and symptoms of abacavir hypersensitivity reactions and directed to immediately contact their clinician if any such reaction occurs. Patients who have interrupted abacavir therapy for reasons other than manifestations of hypersensitivity (e.g., interruption in drug supply) should be advised that severe or fatal hypersensitivity reactions can occur following reintroduction of abacavir, and that abacavir reintroduction should be undertaken only after consultation with their clinician and HLA-B*5701 screening and only with continued monitoring for manifestations of hypersensitivity and if medical care can be readily accessed by the patient or others. To ensure that patients are fully informed regarding these potentially fatal hypersensitivity reactions, a copy of the manufacturer's medication guide and warning card should be dispensed to patients each time they are given a new or refill prescription of abacavir or abacavir-containing preparation and patients should be instructed to read this information and to carry the warning card with them. The medication guide and warning card include information on the potentially life-threatening hypersensitivity reactions that have been reported with abacavir, including information on how to recognize such a reaction if it occurs.

Precautions Related to Use of Fixed Combinations

When abacavir/lamivudine, abacavir/dolutegravir/lamivudine, or abacavir/lamivudine/zidovudine is used, the cautions, precautions, contraindications, and drug interactions associated with each drug in the fixed combination must be considered. Cautionary information applicable to specific populations (e.g., pregnant or nursing women, individuals with hepatic or renal impairment, geriatric patients) should be considered for each drug. For cautionary information related to , , and , see Cautions in the individual drug monographs.

Because the antiretrovirals contained in abacavir/lamivudine, abacavir/dolutegravir/lamivudine, and abacavir/lamivudine/zidovudine also are available in single-entity or other fixed-combination preparations, care should be taken to ensure that therapy is not duplicated when a fixed combination is used in conjunction with other antiretrovirals.

Multiple abacavir-containing preparations should not be used concomitantly.

Abacavir/lamivudine should not be used concomitantly with any preparation containing abacavir or lamivudine. In addition, the fixed combination should not be used concomitantly with any preparation containing emtricitabine.

Abacavir/dolutegravir/lamivudine should not be used concomitantly with any preparation containing abacavir or lamivudine. In addition, the fixed combination should not be used concomitantly with any preparation containing emtricitabine.

Abacavir/lamivudine/zidovudine should not be used concomitantly with any preparation containing abacavir, lamivudine, or zidovudine. In addition, the fixed combination should not be used concomitantly with any preparation containing emtricitabine.

If abacavir/lamivudine, abacavir/dolutegravir/lamivudine, or abacavir/lamivudine/zidovudine is used in HIV-infected patients coinfected with HBV, clinicians should consider that severe, acute exacerbations of HBV infection have been reported following discontinuance of lamivudine in patients coinfected with HIV and HBV. Hepatic function should be closely monitored with clinical and laboratory follow-up for at least several months after abacavir/lamivudine, abacavir/dolutegravir/lamivudine, or abacavir/lamivudine/zidovudine is discontinued in HIV-infected patients coinfected with HBV and, if appropriate, initiation of HBV treatment may be warranted.

If abacavir/lamivudine/zidovudine is used, clinicians should consider that zidovudine has been associated with hematologic toxicity (including neutropenia and severe anemia), particularly in those with advanced HIV-1 disease, and that prolonged zidovudine use has been associated with symptomatic myopathy. Abacavir/lamivudine/zidovudine should be used with caution in patients who have bone marrow compromise evidenced by a granulocyte count less than 1000 cells/mm or a hemoglobin concentration less than 9.5 g/dL.

Other Precautions

Use of abacavir or other NRTIs has been associated with potentially fatal lactic acidosis and severe hepatomegaly with steatosis.(See Cautions: Hepatic Effects and Lactic Acidosis.) Abacavir should be administered with particular caution in patients with known risk factors for liver disease; however, lactic acidosis and severe hepatomegaly with steatosis have been reported in patients with no known risk factors. Abacavir therapy should be interrupted in any patient with clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (signs of hepatotoxicity include hepatomegaly and steatosis even in the absence of marked increases in serum aminotransferase concentrations).

Patients should be advised that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy and that the cause and long-term health effects of these conditions are as yet unknown.(See Cautions: Adipogenic Effects.)

Although there have been conflicting data regarding whether abacavir is associated with an increased risk of MI, an FDA safety analysis did not find an association.(See Cautions: Cardiovascular Effects.) As a precaution in patients receiving antiretroviral therapy (including abacavir), the patient's underlying risk for coronary heart disease (CHD) should be considered and measures taken to address risk factors for CHD (e.g., hypertension, hyperlipidemia, diabetes mellitus, smoking).

A reduction in dosage is recommended if abacavir is used in patients with mild hepatic impairment (Child-Pugh score 5-6).(See Dosage: Dosage in Renal and Hepatic Impairment under Dosage and Administration.) Safety, efficacy, and pharmacokinetics of abacavir have not been established in patients with moderate or severe hepatic impairment and the drug is contraindicated in such patients. Abacavir/lamivudine, abacavir/dolutegravir/lamivudine, and abacavir/lamivudine/zidovudine are not recommended in patients with mild hepatic impairment and are contraindicated in patients with moderate or severe hepatic impairment.

Abacavir in conjunction with other antiretroviral agents is not a cure for HIV infection, and patients receiving the drugs may continue to develop opportunistic infections and other complications associated with HIV disease. Patients should be informed of the critical nature of compliance with HIV therapy and the importance of remaining under the care of a clinician. Patients should be advised to take their antiretroviral regimen exactly as prescribed and to not alter or discontinue the regimen without consulting a clinician.

Patients should be advised that effective antiretroviral regimens can decrease HIV concentrations in blood and genital secretions and strict adherence to such regimens in conjunction with risk-reduction measures may decrease, but cannot absolutely eliminate, the risk of secondary transmission of HIV to others. Patients should continue to practice safer sex (e.g., use latex or polyurethane condoms to minimize sexual contact with body fluids), never share personal items that can have blood or body fluids on them (e.g., toothbrushes, razor blades), and never reuse or share needles.

Pediatric Precautions

Safety and efficacy of single-entity abacavir tablets or oral solution (Ziagen) have not been established in neonates and infants younger than 3 months of age. Use of abacavir in children 3 months of age and older is supported by pharmacokinetic trials and evidence from adequate and well-controlled trials in adults and pediatric patients. Adverse effects reported in children receiving abacavir are similar to those reported in adults receiving the drug (e.g., hypersensitivity reactions, adverse GI effects).

Abacavir/lamivudine (Epzicom) should not be used in pediatric patients weighing less than 25 kg since dosage of the drugs cannot be adjusted individually.

Abacavir/lamivudine/zidovudine (Trizivir) should not be used in pediatric patients weighing less than 40 kg since dosages of the drugs cannot be adjusted individually.

Safety and efficacy of abacavir/dolutegravir/lamivudine (Triumeq) have not been established in pediatric patients.

Geriatric Precautions

While clinical experience to date has not revealed age-related differences in response to abacavir, clinical studies evaluating abacavir have not included sufficient numbers of adults 65 years of age or older to determine whether geriatric patients respond differently than younger adults. Dosage of abacavir for geriatric patients should be selected carefully because of limited experience with the drug in this age group and because these individuals frequently have decreased hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.

Clinical trials of abacavir/lamivudine, abacavir/dolutegravir/lamivudine, and abacavir/lamivudine/zidovudine did not include sufficient numbers of adults 65 years of age or older to determine whether they respond differently than younger adults. The fixed combinations should be used with caution in geriatric patients because of age-related decreases in hepatic, renal, and/or cardiac function and potential for concomitant disease and drug therapy.

Mutagenicity and Carcinogenicity

Abacavir was not mutagenic in bacterial mutagenicity assays (with or without metabolic activation). Abacavir was mutagenic in a L5178Y mouse lymphoma assay without metabolic activation; the drug was not mutagenic in this assay with metabolic activation. In an in vitro cytogenetic study in human lymphocytes, abacavir induced chromosomal aberrations (with or without metabolic activation). Abacavir was clastogenic in male mice, but not in female mice, in an in vivo bone marrow micronucleus assay.

Studies to determine the carcinogenic potential of abacavir were performed in male and female mice and rats using dosages approximately 6-32 times the estimated human exposure based on the recommended human dosage (300 mg twice daily) and resulted in an increase in neoplasms and benign tumors. In mice and rats, neoplasms occurred in the preputial gland in males and in the clitoral gland of females; neoplasms also occurred in the liver of female rats. Benign tumors occurred in the liver and thyroid gland of female rats. The clinical importance of these carcinogenic effects reported in rodents is not known.

Pregnancy, Fertility, and Lactation

Pregnancy

Abacavir crosses the placenta and is distributed into cord blood in concentrations similar to maternal serum concentrations.(See Pharmacokinetics: Distribution.)

Data from the Antiretroviral Pregnancy Registry show no difference in the risk of overall major birth defects for abacavir compared with the background rate for major birth defects in the US reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP). Registry data includes over 2000 prospective reports of abacavir exposures during pregnancy resulting in live births, including over 900 first trimester exposures to the drug.

In reproduction studies in rats, developmental toxicity (i.e., depressed fetal body weight, reduced crown-rump length) and fetal malformations (i.e., fetal anasarca, skeletal malformations) occurred at abacavir dosages associated with exposures 35 times the usual the human exposure (based on AUC). Embryonic and fetal toxicity (i.e., increased resorptions, decreased fetal body weights) and an increased incidence of stillbirth and lower body weights occurred at abacavir dosages associated with exposures approximately 17 times the usual human exposure. In reproduction studies in rabbits, there was no evidence of developmental toxicity and no increase in fetal malformations at abacavir dosages associated with exposure 8.5 times the usual human exposure (based on AUC).

The HHS Panel on Treatment of HIV-infected Pregnant Women and Prevention of Perinatal Transmission states that abacavir in conjunction with lamivudine is a preferred dual NRTI option for initial antiretroviral regimens in antiretroviral-naive pregnant women, but should be used only in those who test negative for the HLA-B*5701 allele.

A triple NRTI regimen of abacavir, lamivudine, and zidovudine is not recommended for initial treatment in antiretroviral-naive pregnant women because of inferior virologic efficacy.

To monitor maternal-fetal outcomes of pregnant women exposed to antiretroviral agents, including abacavir, the Antiretroviral Pregnancy Registry was established. Clinicians are encouraged to contact the registry at 800-258-4263 or http://www.APRegistry.com to report cases of prenatal exposure to antiretroviral drugs.

Fertility

There was no evidence that abacavir affected fertility or reproductive performance in male or female rats when the drug was given in a dosage associated with exposures approximately 8 times the usual human exposure (based on body surface area).

Lactation

Abacavir is distributed into human milk and has been detected in the plasma of at least one breast-feeding child.(See Pharmacokinetics: Distribution.)

Because of the risk of transmission of HIV to an uninfected infant through breast milk, the US Centers for Disease Control and Prevention (CDC) and other experts recommend that HIV-infected women not breast-feed infants, regardless of antiretroviral therapy. Therefore, because of the potential for HIV transmission and the potential for serious adverse effects from abacavir if the drug were distributed into milk, women should be instructed not to breast-feed while they are receiving abacavir.

Drug Interactions

The following drug interactions are based on studies using abacavir sulfate. Drug interaction studies have not been performed to date using the fixed combination containing abacavir and lamivudine (abacavir/lamivudine), fixed combination containing abacavir, dolutegravir, and lamivudine (abacavir/dolutegravir/lamivudine), or fixed combination containing abacavir, lamivudine, and zidovudine (abacavir/lamivudine/zidovudine). When a fixed combination is used, interactions associated with each drug in the fixed combination should be considered.

Drugs Affecting Hepatic Microsomal Enzymes

In vitro studies indicate that abacavir does not inhibit the cytochrome P-450 (CYP) isoenzymes 2C9, 2D6, or 3A4. Therefore, clinically important drug interactions between abacavir and drugs metabolized by these isoenzymes are not expected.

Alcohol

Although alcohol and abacavir are both metabolized by alcohol dehydrogenase, clinically important drug interactions are not expected between abacavir and alcohol. Following oral administration of a single oral dose of abacavir 600 mg and alcohol 0.7 g/kg (about 5 alcoholic drinks) in HIV-infected men, the area under the plasma concentration-time curve (AUC) of abacavir was increased 41% and the elimination half-life of the drug was increased 26%. There was no change in the pharmacokinetic parameters of alcohol and no evidence of disulfiram-type reactions in any of the men. Concomitant use of abacavir and alcohol has not been investigated in women.

Antiretroviral Agents

HIV Entry and Fusion Inhibitors

There is no in vitro evidence of antagonistic antiretroviral effects between maraviroc and abacavir.

HIV Integrase Inhibitors (INSTIs)

Raltegravir and abacavir are additive or synergistic against HIV-1 in vitro. There is no in vitro evidence of antagonistic antiretroviral effects between abacavir and dolutegravir or elvitegravir.

Elvitegravir

Concomitant use of abacavir and elvitegravir, ritonavir-boosted elvitegravir, or cobicistat-boosted elvitegravir did not result in clinically important drug interactions.

HIV Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs)

The antiretroviral effects of abacavir and nonnucleoside reverse transcriptase inhibitors (NNRTIs), including efavirenz and nevirapine, are additive or synergistic against HIV-1 in vitro. There is no in vitro evidence of antagonistic antiretroviral effects between abacavir and etravirine, nevirapine, or rilpivirine.

Although specific studies have not been performed, clinically important pharmacokinetic interactions between abacavir and delavirdine, efavirenz, nevirapine, or rilpivirine are not expected.

HIV Nucleoside and Nucleotide Reverse Transcriptase Inhibitors (NRTIs)

Results of in vitro studies using HIV-1 indicate that the antiretroviral effects of abacavir are not antagonized by other nucleoside reverse transcriptase inhibitors (NRTIs), including didanosine, emtricitabine, lamivudine, stavudine, tenofovir disoproxil fumarate (tenofovir DF), and zidovudine.

Lamivudine and Zidovudine

Clinically important pharmacokinetic interactions have not been observed when abacavir, lamivudine, and zidovudine were used concurrently. In a crossover study evaluating concomitant use of single doses of abacavir (600 mg), lamivudine (150 mg), and zidovudine (300 mg) in HIV-infected individuals, the pharmacokinetic parameters of abacavir were unchanged when administered with lamivudine and/or zidovudine. The AUC of lamivudine was decreased 15% and the AUC of zidovudine increased 10% when used concomitantly with abacavir.

Tenofovir

Concomitant use of tenofovir DF (300 mg once daily) and abacavir (single 300-mg dose) resulted in a 12% increase in peak plasma concentrations of abacavir, but did not affect the AUC of abacavir; peak plasma concentrations and AUC of tenofovir were not affected.

HIV Protease Inhibitors (PIs)

Abacavir and some HIV protease inhibitors (PIs) (e.g., amprenavir [commercially available as fosamprenavir], nelfinavir, tipranavir) are additive or synergistic against HIV-1 in vitro. There is no in vitro evidence of antagonistic antiretroviral effects between abacavir and amprenavir, atazanavir, or darunavir.

Darunavir

Although specific data are not available, pharmacokinetic interactions between abacavir and darunavir are not expected.

Fosamprenavir

A pharmacokinetic interaction between abacavir and fosamprenavir is unlikely.

Lopinavir

Although the clinical importance is unclear, lopinavir may induce glucuronidation, and concomitant use of abacavir and the fixed combination of lopinavir and ritonavir (lopinavir/ritonavir) has the potential to reduce plasma abacavir concentrations.

Tipranavir

Concomitant use of abacavir and ritonavir-boosted tipranavir results in a 35-44% decrease in the AUC of abacavir. The clinical importance of this pharmacokinetic interaction is not known, and appropriate dosages for concomitant use with respect to safety and efficacy have not been established.

HCV Antivirals

HCV Protease Inhibitors

Simeprevir

Clinically important pharmacokinetic interactions are not expected if abacavir is used concomitantly with simeprevir.

HCV Replication Complex Inhibitors

Elbasvir and Grazoprevir

Clinically important pharmacokinetic interactions are not expected if abacavir is used concomitantly with the fixed combination of elbasvir and grazoprevir (elbasvir/grazoprevir).

Ledipasvir and Sofosbuvir

Clinically important pharmacokinetic interactions are not expected if abacavir is used concomitantly with the fixed combination of ledipasvir and sofosbuvir (ledipasvir/sofosbuvir).

Opiates and Opiate Partial Agonists

Methadone

Concomitant use of methadone and abacavir may increase clearance of methadone, but does not affect the pharmacokinetics of abacavir. In a limited number of HIV-infected individuals receiving maintenance therapy with methadone (40 or 90 mg daily), concomitant use of abacavir 600 mg twice daily (twice the usual recommended adult dosage) resulted in a 22% increase in methadone clearance.

Some experts state that dosage adjustments are not necessary in patients receiving methadone and abacavir concomitantly. The manufacturer of abacavir states that, although an increase in methadone dosage may be required in a small number of patients because of a pharmacokinetic interaction, most patients will not need modification of methadone dosage.

Ribavirin

In vitro, ribavirin had no effect on the antiretroviral activity of abacavir against HIV-1.

Pharmacokinetics

The pharmacokinetics of abacavir have been studied in adults with human immunodeficiency virus (HIV) infection and in HIV-infected children 3 months to 13 years of age.

There is some evidence from a multiple-dose study that mean peak plasma concentrations and area under the concentration-time curve (AUC) of abacavir may be 30 and 54% higher, respectively, in women than in men. However, in a population pharmacokinetic analysis, there was no gender difference in abacavir AUC normalized for lean body weight. Further study is needed to more fully evaluate the pharmacokinetics of abacavir during pregnancy. In one study, the AUC of abacavir was similar in pregnant and nonpregnant women, but peak plasma concentrations of the drug were slightly decreased and there was greater variability in AUC and oral clearance during pregnancy. Abacavir pharmacokinetics are similar between blacks and Caucasians.

Pharmacokinetics of abacavir have not been specifically studied in geriatric adults older than 65 years of age. In addition, only limited information is available on the pharmacokinetics of abacavir in individuals with renal or hepatic impairment.

The manufacturer states that commercially available abacavir sulfate tablets and oral solution are bioequivalent. In pediatric patients, abacavir exposure is expected to be similar regardless of whether the scored tablet or oral solution is administered.

A fixed-combination tablet containing abacavir 600 mg and lamivudine 300 mg (Epzicom) is bioequivalent to two 300-mg tablets of abacavir and two 150-mg tablets of lamivudine given simultaneously. Results of a crossover study in fasting, healthy adults indicate that a fixed-combination tablet containing 300 mg of abacavir, 150 mg of lamivudine, and 300 mg of zidovudine (Trizivir) is bioequivalent to a 300-mg tablet of abacavir, a 150-mg tablet of lamivudine, and a 300-mg tablet of zidovudine administered simultaneously.

In some early studies evaluating the pharmacokinetics of abacavir, the drug was administered orally as the succinate salt (a formulation not commercially available in the US).

Dosages and concentrations of abacavir sulfate or abacavir succinate are expressed in terms of the base.

Absorption

Abacavir is rapidly absorbed following oral administration as the succinate or sulfate salts. The geometric mean absolute oral bioavailability of abacavir sulfate tablets is 83%. Studies using oral abacavir succinate (not commercially available in the US) indicate that peak plasma concentrations of the drug generally are attained 0.5-1.7 hours after a dose.

In HIV-infected adults receiving abacavir in a dosage of 300 mg twice daily (given as abacavir succinate), peak plasma concentration and AUC (0-12 hours) of the drug at steady-state averaged 3 mcg/mL and 6.02 mcg&bul;hour/mL, respectively. In studies in HIV-infected adults employing oral abacavir dosages of 300-1200 mg daily (given as abacavir succinate), the pharmacokinetics of the drug were independent of the dose; results of studies using abacavir succinate indicate that increases in mean peak plasma concentration and AUC are not precisely proportional to dosage increases.

In HIV-infected children 3 months to 13 years of age who received 8 mg/kg of abacavir every 12 hours (given as an oral solution containing abacavir sulfate), steady-state peak plasma concentration and AUC of the drug averaged 3.71 mcg/mL and 9.8 mcg&bul;hour/mL, respectively. Steady-state AUC in those 3 months to 2 years of age, older than 2 to 6 years of age, or older than 6 to 13 years of age averaged 8.67, 9.38, or 10.71 mcg&bul;hour/mL, respectively. Pediatric patients receiving abacavir oral solution at the recommended dosage achieved plasma concentrations similar to those observed in adults; pediatric patients receiving abacavir oral tablets achieved plasma concentrations higher than those observed in pediatric patients receiving abacavir oral solution. In HIV-1-infected pediatric patients 3 months to 12 years of age, the AUC of abacavir reported in those receiving the oral solution or tablets administered once daily was comparable to the AUC reported in those receiving the same total daily dosage of the oral solution or tablets administered twice daily. Mean peak plasma concentrations reported with a once-daily regimen were 1.6- to 2.3-fold higher than those reported with a twice-daily regimen.

The pharmacokinetics of abacavir in pregnant women is similar to that reported in nonpregnant women; the AUC of the drug in pregnant women is similar to that reported in women 6-12 weeks postpartum and in nonpregnant individuals.

The pharmacokinetics of abacavir have been evaluated in patients with mild hepatic impairment (Child-Pugh score 5-6) and results indicate a mean increase of 89% in the AUC of the drug following a single 600-mg dose. Although the AUCs of metabolites of the drug were not affected by mild hepatic impairment, there was a decrease in the rates of formation and elimination of these metabolites. The pharmacokinetics of abacavir have not been studied in patients with moderate or severe hepatic impairment.

Food

Presence of food in the GI tract does not have a clinically important effect on bioavailability of abacavir.

In a study in HIV-infected individuals who received a single 300-mg dose of abacavir (given as tablets containing abacavir sulfate), administration with food decreased peak plasma concentration 35% but decreased the AUC of the drug by only 5% compared with administration in the fasting state.

In a single-dose bioavailability study, food did not affect the extent of absorption of abacavir or lamivudine when the drugs were given as the commercially available fixed-combination tablet containing 600 mg of abacavir and 300 mg of lamivudine. In a crossover study in healthy adults, food did not affect the extent of absorption of abacavir, lamivudine, or zidovudine when the drugs were given as the commercially available fixed-combination tablet containing 300 mg of abacavir, 150 mg of lamivudine, and 300 mg of zidovudine (abacavir/lamivudine/zidovudine).

In a study in healthy adults using abacavir/dolutegravir/lamivudine, administration of the fixed combination with a high-fat meal decreased abacavir peak plasma concentrations by 23% and increased peak plasma concentrations and AUC of dolutegravir by 37 and 48%, respectively, compared with administration in the fasting state; lamivudine exposures were not affected.

Distribution

Following oral administration, abacavir is extensively distributed. The apparent volume of distribution of the drug following IV administration in HIV-infected adults is 0.86 L/kg, suggesting distribution into extravascular spaces.

Following systemic administration, abacavir distributes into erythrocytes and CD4 CEM cells by nonfacilitated diffusion. Following administration of radiolabeled abacavir, total blood- and plasma-drug related radioactivity are identical; these results indicate abacavir readily distributes into erythrocytes.

Abacavir is distributed into CSF. In HIV-infected adults receiving an antiretroviral regimen that included abacavir (usually 300 mg of abacavir twice daily), median CSF or plasma concentrations of the drug were 0.128 mcg/mL or 0.139 mcg/mL, respectively, and the estimated CSF half-life was 2.5 hours.

Abacavir is about 50% bound to plasma proteins; binding of abacavir to plasma proteins is independent of drug concentration.

Abacavir crosses the placenta. In several HIV-infected pregnant women who were receiving abacavir as part of a multiple-drug regimen, concentrations of the drug in cord blood were 0.21-1.8 mcg/mL and maternal serum concentrations were 0.15-1.83 in samples obtained at the time of delivery.

Abacavir is distributed into human milk. In a study in 15 women receiving abacavir at 1 month postpartum, the drug was distributed into milk (milk-to-plasma ratio of 0.85) and also was detected in the plasma of at least one breast-feeding child.

Elimination

The plasma elimination half-life of abacavir following a single oral dose (given as abacavir sulfate) is about 1.5 hours. In HIV-infected children 3 months to 13 years of age who received 8 mg/kg of abacavir every 12 hours (given as an oral solution containing abacavir sulfate), steady-state plasma elimination half-life averaged 1.3 hours and was essentially the same as that reported after a single dose. Following IV administration of abacavir in adults, total clearance reportedly is 0.8 L/hour per kg.

In patients with mild hepatic impairment (Child-Pugh score 5-6), there is an increase of 58% in the half-life of abacavir after a single 600-mg dose of the drug. Following oral administration of a single 300-mg dose of abacavir to an individual with renal failure (glomerular filtration rate less than 10 mL/minute) undergoing peritoneal dialysis, the plasma elimination half-life of the drug was 1.33 hours.

Intracellularly, abacavir is phosphorylated to abacavir monophosphate by adenosine phosphotransferase; abacavir monophosphate is then converted to carbovir monophosphate in a reaction catalyzed by cytosolic enzymes and then to carbovir triphosphate by cellular kinases. Intracellular (host cell) conversion of abacavir to carbovir triphosphate is necessary for the antiviral activity of the drug. The in vitro intracellular half-life of carbovir triphosphate in CD4 CEM cells is 3.3 hours.

Abacavir is metabolized by alcohol dehydrogenase to form the 5'-carboxylic acid and by glucuronyltransferase to form the 5'-glucuronide; these metabolites do not appear to have any antiviral activity. Any involvement of cytochrome P-450 isoenzymes in the metabolism of abacavir is limited.

Following oral administration of a 600-mg dose of radiolabeled abacavir, 82.2% of the dose is excreted in urine and 16% of the dose is excreted in feces. The 5'-carboxylic acid metabolite, 5'-glucuronide metabolite, and unchanged abacavir accounted for 30, 36, and 1.2%, respectively, of recovered radioactivity in urine; unidentified minor metabolites accounted for 15% of recovered radioactivity in urine.

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